Tyr-701 is a new regulatory site for neurotrophin receptor TrkA trafficking and function
Tyr-701 is a new regulatory site for neurotrophin receptor TrkA trafficking and function
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DOI：
10.1111/j.1471-4159.2007.05027.x
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发表时间：
2008-01-01
影响因子：
4.7
通讯作者：
Lloveral, Marta
中科院分区：
文献类型：
--
作者：
de Pablo, Yolanda;Perez-Garcia, M. Jose;Lloveral, Marta
原肌球蛋白相关激酶 A (TrkA) 受体介导神经生长因子对神经元细胞的几个亚群产生的影响。配体与 TrkA 结合诱导受体几个酪氨酸残基的自磷酸化和信号级联的激活。在这项研究中，我们描述了一个与 TrkA 调节相关的新位点，酪氨酸 701 (Y701)，它对于受体运输和激活很重要。用天冬氨酸或苯丙氨酸替代 Y701 会降低受体内化率，并降低 TrkA 与网格蛋白重链的共定位和关联，表明 Y701 构成与受体内吞作用调节相关的 Yxx Phi (YRKF701-704) 运输基序。根据这一假设，Y701突变受体与溶酶体标记物的共定位也减少，支持YRKF701-704基序参与TrkA受体的溶酶体靶向。与预期相反，尽管突变受体保留了其体外激酶活性，但为了模拟磷酸化而用 Y701 替换 Asp 会损害 TrkA 介导神经生长因子诱导分化的能力。这是 Tyr 残基可以同时调节 TrkA 受体运输和活性的第一个证据。
Tropomyosin-related kinase A (TrkA) receptor mediates the effects exerted by nerve growth factor on several subpopulations of neuronal cells. Ligand binding to TrkA induces receptor autophosphorylation on several tyrosine residues and the activation of signaling cascades. In this study, we describe a new site relevant for TrkA regulation, the tyrosine 701 (Y701), which is important for receptor trafficking and activation. Y701 replacement by aspartate or phenylalanine reduces receptor internalization rate and decreases the colocalization and association of TrkA with clathrin heavy chain, demonstrating that Y701 constitutes a Yxx Phi (YRKF701-704) trafficking motif relevant for the regulation of receptor endocytosis. In accordance with this hypothesis, the colocalization of Y701 mutant receptors with a lysosomal marker is also reduced giving support to the involvement of the YRKF701-704 motif in the lysosomal targeting of TrkA receptors. Contrary to what was expected, substitution of Y701 for an Asp in order to mimic phosphorylation, impairs TrkA ability to mediate nerve growth factor-induced differentiation, although the mutant receptor retains its in vitro kinase activity. This is the first evidence that a Tyr residue can simultaneously regulate TrkA receptor trafficking and activity.